Zolvera 40mg / 5ml Oral Solution

1. Name Of The Medicinal Product

ZOLVERA 40mg/5ml Oral Solution

2. Qualitative And Quantitative Composition

Verapamil Hydrochloride 40mg/5ml

For excipients see Section 6.1

3. Pharmaceutical Form

Oral Solution

4. Clinical Particulars

4.1 Therapeutic Indications

1. Treatment of mild to moderate hypertension.

2. Treatment and prophylaxis of chronic stable angina, vasospastic angina and unstable angina.

3. Treatment and prophylaxis of paroxysmal supraventricular tachycardia and the reduction of ventricular rate in atrial flutter/fibrillation. Verapamil should not be used when atrial flutter/fibrillation complicates Wolff-Parkinson-White syndrome (see Contraindications).

4.2 Posology And Method Of Administration

Adults:

Hypertension: Initially 120mg b.d. increasing to 160mg b.d. when necessary. In some cases, dosages of up to 480mg daily, in divided doses, have been used. A further reduction in blood pressure may be obtained by combining verapamil with other antihypertensive agents, in particular diuretics. For concomitant administration with beta-blockers see Precautions.

Angina: 120mg t.d.s. is recommended. 80mg t.d.s. can be completely satisfactory in some patients with angina of effort. Less than 120mg t.d.s is not likely to be effective in variant angina.

Supraventricular tachycardias: 40-120mg, t.d.s. according to the severity of the condition.

Hepatic Impairment: Verapamil is extensively metabolised in liver and for those patients with impaired liver function, the dose should be reduced and carefully titrated.

Renal Impairment: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil should be prescribed cautiously when renal function is impaired. Careful patient monitoring is recommended.

Children:

Up to 2 years: 20mg, 2-3 times a day.

2 years and above: 40-120mg, 2-3 times a day, according to age and effectiveness.

Elderly:

The adult dose is recommended unless liver or renal function is impaired (see Precautions).

4.3 Contraindications

Hypersensitivity to verapamil or any of the ingredients

Cardiogenic shock

Acute myocardial infarction complicated by bradycardia, hypotension or left ventricular failure

Second or third degree atrioventricular block

Sino-atrial block

Sick sinus syndrome

Uncompensated heart failure

Bradycardia of less than 50 beats/minute (Except in patients with functioning artificial ventricular pacemaker)

Intravenous dantrolene (See section 4.5)

Hypotension of less than 90m Hg systolic

Atrial flutter or fibrillation associated with an accessory pathway (e.g. Wolff-Parkinson-White syndrome, Lown-Ganong-Levine syndrome)

Porphyria

Concomitant ingestion of grapefruit juice.

4.4 Special Warnings And Precautions For Use

Since verapamil is extensively metabolised in the liver, careful dose titration of verapamil is required in patients with liver disease. The disposition of verapamil in patients with renal impairment has not been fully established and therefore careful patient monitoring is recommended. Verapamil is not removed during dialysis.

Verapamil may affect impulse conduction and therefore verapamil solution should be used with caution in patients with first degree AV block. Patients with atrial flutter/fibrillation in association with an accessory pathway (e.g. WPW syndrome) may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.

Verapamil may affect left ventricular contractility; this effect is small and normally not important but cardiac failure may be precipitated or aggravated.

In patients with incipient cardiac failure, therefore, verapamil should be given only after such cardiac failure has been controlled with appropriate therapy, e.g. digitalis.

When treating hypertension with verapamil, monitoring of the patient's blood pressure at regular intervals is required.

This product also contains liquid maltitol. Patients with rare hereditary problems of fructose should not take this medicine.

Verapamil is extensively metabolised in the liver and special care should be taken in cases where liver damage exists, as plasma levels of verapamil may be increased (See section 4.2)

Caution should be exercised in treatment with HMG CoA reductase inhibitors (e.g. simvastatin, atorvastatin or lovastatin) for patients taking verapamil. These patients should be started on the lowest possible dose of verapamil and titrated upwards. If verapamil treatment is to be added to patients already taking HMG CoA reductase inhibitor (e.g. simvastatin, atorvastatin or lovastatin), refer to the advice in the respective statin product information.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro metabolic studies indicate that verapamil hydrochloride is metabolised by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 (such as ketoconazole, erythromycin and ritonavir) causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.

Interactions between verapamil and the following medications have been reported:

Digoxin: Verapamil has been shown to increase the serum concentration of digoxin and caution should be exercised with regard to digitalis toxicity. The digitalis level should be determined and the glycoside dose reduced, if required.

Beta-blockers, anti-arrhythmic agents or inhaled anaesthetics: The combination with verapamil may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure). Intravenous beta-blockers should not be given to patients under treatment with verapamil.

Carbamazepine, ciclosporin, midazolam, and theophylline: Use of verapamil has resulted in increased serum levels of these medications, which could lead to increased side effects.

Rifampicin, phenytoin and phenobarbital: Serum levels of verapamil are reduced.

Lithium: Serum levels of lithium may be reduced (pharmacokinetic effect); there may be increased sensitivity to lithium causing enhanced neurotoxicity (pharmacodynamic effect).

Cimetidine: Increase in verapamil serum level is possible.

Neuromuscular blocking agents employed in anaesthesia: The effects may be potentiated. The effects of verapamil may be additive to other hypotensive agents.

Sirolimus: Plasma concentration of both drugs may be increased.

Intravenous dantrolene: The association of this muscle relaxant given intravenously and verapamil is potentially dangerous (can cause fatal ventricular fibrillation in animals) and is contraindicated.

HMG Co-A Reductase Inhibitors (Statins): Verapamil may increase the plasma concentrations of simvastatin, atorvastatin and lovastatin. Treatment with HMG CoA reductase inhibitors (e.g. simvastatin, atorvastatin or lovastatin) in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. If verapamil treatment is to beaded to patients already taking an HMG CoA reductase inhibitor (e.g. simvastatin, atorvastatin or lovastatin), consider a reduction in the statin dose and re-titrate against serum cholesterol concentrations.

There is no direct in vivo clinical evidence of an interaction between atorvastatin and verapamil; however there is a strong potential for verapamil to significantly affect atorvastatin pharmacokinetics in a similar manner to simvastatin or lovastatin. Consider using caution when atorvastatin and verapamil are concomitantly administered.

Fluvastatin, pravastatin and rosuvastatin are not metabolised by CYP 3A4 and are less likely to interact with verapamil.

Alcohol: Plasma concentration may be increased (see Effects on ability to drive and use machines)

Grapefruit Juice: An increase in verapamil levels has been reported.

4.6 Pregnancy And Lactation

Although animal studies have not shown any teratogenic effects, verapamil should not be given during the first trimester of pregnancy unless, in the clinician's judgement, it is essential for the welfare of the patient.

Verapamil is excreted into the breast milk in small amounts and is unlikely to be harmful. However, rare hypersensitivity reactions have been reported with verapamil and, therefore, it should only be used during lactation if, in the clinician's judgement, it is essential for the welfare of the patient.

4.7 Effects On Ability To Drive And Use Machines

Depending on individual susceptibility, the patient's ability to drive a vehicle or operate machinery or work under hazardous conditions may be impaired. This is particularly true in the initial stages of treatment, or when changing over from another medication. Like many other common medicines, verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

4.8 Undesirable Effects

Verapamil is generally well tolerated. Side effects are usually mild and transient and discontinuation of therapy is rarely necessary.

Immune System Disorders: Allergic reactions (e.g. erythema, pruritus, urticaria, Quincke's oedema, Stevens-Johnson syndrome, erythema multiforme, alopecia and purpura) are very rarely seen.

Nervous System Disorders: Tremor and extrapyramidal syndrome. Headaches and dizziness have been reported rarely. Paraesthesia may occur.

Ear and Labyrinth Disorders: Vertigo and tinnitus.

Cardiac Disorders: Particularly when given in high doses or in the presence of previous myocardial damage, some cardiovascular effects of verapamil may occasionally be greater than therapeutically desired: bradycardic arrhythmias, such as sinus bradycardia, sinus arrest with asystole, second and third degree AV block, bradyarrhythmia in atrial fibrillation, palpitations, tachycardia, development or aggravation of heart failure.

Vascular Disorders: Peripheral oedema, hypotension. Flushing is observed occasionally. Erythromelalgia may occur.

Gastrointestinal Disorders: Constipation may occur. Nausea, vomiting, ileus, abdominal pain/discomfort have been reported rarely.

Gingival hyperplasia may very rarely occur when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued.

Hepatobiliary Disorders: A reversible impairment of liver function, characterised by an increase in transaminase and/or alkaline phosphatase may occur on very rare occasions during verapamil treatment and is most probably a hypersensitivity reaction.

Musculoskeletal and Connective Tissue Disorders: In very rare cases, there may be myalgia and arthralgia.

Reproductive System and Breast Disorders: Impotence (erectile dysfunction) has been rarely reported and isolated cases of galactorrhoea. On very rare occasions, gynaecomastia has been observed in elderly male patients under long-term verapamil treatment, which was fully reversible in all cases when the drug was discontinued.

Rises in prolactin levels have been reported.

General Disorders and Administration Site Conditions: Fatigue and ankle oedema have been reported rarely.

4.9 Overdose

The course of symptoms in verapamil intoxication depends on the amount taken, the point in time at which detoxification measures are taken and myocardial contractility (age-related).

The main symptoms are as follows: blood pressure fall (at times to values not detectable), shock symptoms, loss of consciousness, first and second degree AV block (frequently as Wenckebach's phenomenon with or without escape rhythms), total AV block with total AV dissociation, escape rhythm, asystole, sinus bradycardia, sinus arrest hyperglycaemia, stupor and metabolic acidosis. Fatalities have occurred as a result of overdose. The therapeutic measures to be taken depend on the point in time at which verapamil was taken and the type and severity of intoxication symptoms. Gastric lavage, taking the usual precautionary measures may be appropriate even later than 12 hours after ingestion, if no gastrointestinal motility (peristaltic sounds) is detectable.

The usual intensive resuscitation measures, such as extrathoracic heart massage, respiration, defibrillation and/or pacemaker therapy. Specific measures to be taken: Elimination of cardiodepressive effects, hypotension or bradycardia. The specific antidote is calcium, e.g. 10-20ml of a 10% calcium gluconate solution administered intravenously (2.25 - 4.5mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5mmol/hour).

The following measures may also be necessary: In case of second and third degree AV block, sinus bradycardia, asystole: atropine, isoprenaline, orciprenaline or pacemaker therapy. In case of hypotension after appropriate positioning of the patient: dopamine, dobutamine, noradrenaline. If there are signs of continuing myocardial failure: dopamine, dobutamine, cardiac glycosides or if necessary, repeated calcium gluconate injections.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Verapamil is a calcium antagonist which blocks the inward movement of calcium ions in cardiac muscle cells, in smooth muscle cells of the coronary and systemic arteries and in the cells of the intracardiac conduction system. Verapamil lowers peripheral vascular resistance with no reflex tachycardia. Its efficacy in reducing both raised systolic and diastolic blood pressure is thought to be due to this mode of action. The decrease in systemic and coronary vascular resistance and the sparing effect on intracellular oxygen consumption appear to explain the anti-anginal properties of the drug. Because of its effect on the movement of calcium in the intracardiac conduction system, verapamil reduces automaticity, decreases conduction velocity and increases the refractory period.

5.2 Pharmacokinetic Properties

Over 90% of verapamil is absorbed following administration with peak plasma concentrations occurring between 1 and 2 hours and does not appear to be affected markedly by food.

Verapamil is subject to pre-systemic hepatic metabolism with up to 80% of the dose eliminated this way. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, absolute bioavailability ranges from 20-35%. Verapamil is widely distributed throughout the body with a distribution half-life of 15-30 mins. Verapamil is 90% bound to plasma proteins, mainly to albumin and

5.3 Preclinical Safety Data

Verapamil is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene glycol, benzoic acid, liquid maltitol, dill water concentrate, liquorice flavour, citric acid monohydrate, sodium citrate and purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months

3 months once open

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Bottle: Amber (Type III) glass

Closures: a) Aluminium, EPE wadded, roll-on pilfer proof screw cap.

b) HDPE, EPE wadded, tamper evident screw cap.

c) HDPE, EPE wadded, tamper evident, child resistant closure.

Pack Size: 150ml

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd, Rosemont House, Yorkdale Industrial Park, Braithwaite Street, Leeds, LS11 9XE, UK.

8. Marketing Authorisation Number(S)

PL 00427/0130

9. Date Of First Authorisation/Renewal Of The Authorisation

23 May 2001/23/02/2007

10. Date Of Revision Of The Text

JUNE 2009